DTR Bandit: Learning to Make Response-Adaptive Decisions With Low Regret

Dynamic treatment regimes (DTRs) are personalized, adaptive, multi-stage treatment plans that adapt treatment decisions both to an individual's initial features and to intermediate outcomes and features at each subsequent stage, which are affected by decisions in prior stages. Examples include personalized first- and second-line treatments of chronic conditions like diabetes, cancer, and depression, which adapt to patient response to first-line treatment, disease progression, and individual characteristics. While existing literature mostly focuses on estimating the optimal DTR from offline data such as from sequentially randomized trials, we study the problem of developing the optimal DTR in an online manner, where the interaction with each individual affect both our cumulative reward and our data collection for future learning. We term this the DTR bandit problem. We propose a novel algorithm that, by carefully balancing exploration and exploitation, is guaranteed to achieve rate-optimal regret when the transition and reward models are linear. We demonstrate our algorithm and its benefits both in synthetic experiments and in a case study of adaptive treatment of major depressive disorder using real-world data

Review of precision cancer medicine: Evolution of the treatment paradigm.

In recent years, biotechnological breakthroughs have led to identification of complex and unique biologic features associated with carcinogenesis. Tumor and cell-free DNA profiling, immune markers, and proteomic and RNA analyses are used to identify these characteristics for optimization of anticancer therapy in individual patients. Consequently, clinical trials have evolved, shifting from tumor type-centered to gene-directed, histology-agnostic, with innovative adaptive design tailored to biomarker profiling with the goal to improve treatment outcomes. A plethora of precision medicine trials have been conducted. The majority of these trials demonstrated that matched therapy is associated with superior outcomes compared to non-matched therapy across tumor types and in specific cancers. To improve the implementation of precision medicine, this approach should be used early in the course of the disease, and patients should have complete tumor profiling and access to effective matched therapy. To overcome the complexity of tumor biology, clinical trials with combinations of gene-targeted therapy with immune-targeted approaches (e.g., checkpoint blockade, personalized vaccines and/or chimeric antigen receptor T-cells), hormonal therapy, chemotherapy and/or novel agents should be considered. These studies should target dynamic changes in tumor biologic abnormalities, eliminating minimal residual disease, and eradicating significant subclones that confer resistance to treatment. Mining and expansion of real-world data, facilitated by the use of advanced computer data processing capabilities, may contribute to validation of information to predict new applications for medicines. In this review, we summarize the clinical trials and discuss challenges and opportunities to accelerate the implementation of precision oncology

Metabolomic evaluation of Mitomycin C and rapamycin in a personalized treatment of pancreatic cancer

In a personalized treatment designed for a patient with pancreatic cancer resistant to other treatments, the success of Mitomycin C (MMC) has been highlighted. This was revealed in a murine xenograft tumor model encompassing pancreatic adenocarcinoma cells extracted from the patient. The patient was found to exhibit a biallelic inactivation of the PALB2 gene, involved in DNA repair in addition to another mutation in the TSC2 gene that induces susceptibility of the tumor to therapeutic targets of the PI3K-mTOR pathway. The aim of the study was to apply metabolomics to elucidate the modes of action of each therapy, suggesting why MMC was so successful in this patient and why it could be a more popular choice in future pancreatic cancer treatment. The effectiveness of MMC compared to rapamycin (RM), another relevant therapeutic agent has been evaluated through liquid- and gas-chromatography mass spectrometry-based metabolomic analyses of the xenograft tumors. The relative concentrations of many metabolites in the xenograft tumors were found to be increased by MMC relative to other treatments (RM and a combination of both), including a number that are involved in central carbon metabolism (CCM). Metabolic fingerprinting revealed statistically significantly altered pathways including, but not restricted to, the pentose phosphate pathway, glycolysis, TCA cycle, purine metabolism, fatty acid biosynthesis, in addition to many significant lipid and amino acid alterations. Given the genetic background of the patient, it was expected that the combined therapy would be most effective; however, the most effective was MMC alone. It is proposed that the effectiveness of MMC is owed to its direct effect on CCM, a vital region of tumor metabolism

Blackboard to Bedside: A Mathematical Modeling Bottom-Up Approach Toward Personalized Cancer Treatments

Cancers present with high variability across patients and tumors; thus, cancer care, in terms of disease prevention, detection, and control, can highly benefit from a personalized approach. For a comprehensive personalized oncology practice, this personalization should ideally consider data gathered from various information levels, which range from the macroscale population level down to the microscale tumor level, without omission of the central patient level. Appropriate data mined from each of these levels can significantly contribute in devising personalized treatment plans tailored to the individual patient and tumor. Mathematical models of solid tumors, combined with patient-specific tumor profiles, present a unique opportunity to personalize cancer treatments after detection using a bottom-up approach. Here, we discuss how information harvested from mathematical models and from corresponding in silico experiments can be implemented in preclinical and clinical applications. To conceptually illustrate the power of these models, one such model is presented, and various pertinent tumor and treatment scenarios are demonstrated in silico. The presented model, specifically a multiscale, hybrid cellular automaton, has been fully validated in vitro using multiple cell-line–specific data. We discuss various insights provided by this model and other models like it and their role in designing predictive tools that are both patient, and tumor specific. After refinement and parametrization with appropriate data, such in silico tools have the potential to be used in a clinical setting to aid in treatment protocols and decision making.Publisher PDFPeer reviewe

The Master Observational Trial: A New Class of Master Protocol to Advance Precision Medicine.

This commentary introduces a new clinical trial construct, the Master Observational Trial (MOT), which hybridizes the power of molecularly based master interventional protocols with the breadth of real-world data. The MOT provides a clinical venue to allow molecular medicine to rapidly advance, answers questions that traditional interventional trials generally do not address, and seamlessly integrates with interventional trials in both diagnostic and therapeutic arenas. The result is a more comprehensive data collection ecosystem in precision medicine

ConfidentCare: A Clinical Decision Support System for Personalized Breast Cancer Screening

Breast cancer screening policies attempt to achieve timely diagnosis by the regular screening of apparently healthy women. Various clinical decisions are needed to manage the screening process; those include: selecting the screening tests for a woman to take, interpreting the test outcomes, and deciding whether or not a woman should be referred to a diagnostic test. Such decisions are currently guided by clinical practice guidelines (CPGs), which represent a one-size-fits-all approach that are designed to work well on average for a population, without guaranteeing that it will work well uniformly over that population. Since the risks and benefits of screening are functions of each patients features, personalized screening policies that are tailored to the features of individuals are needed in order to ensure that the right tests are recommended to the right woman. In order to address this issue, we present ConfidentCare: a computer-aided clinical decision support system that learns a personalized screening policy from the electronic health record (EHR) data. ConfidentCare operates by recognizing clusters of similar patients, and learning the best screening policy to adopt for each cluster. A cluster of patients is a set of patients with similar features (e.g. age, breast density, family history, etc.), and the screening policy is a set of guidelines on what actions to recommend for a woman given her features and screening test scores. ConfidentCare algorithm ensures that the policy adopted for every cluster of patients satisfies a predefined accuracy requirement with a high level of confidence. We show that our algorithm outperforms the current CPGs in terms of cost-efficiency and false positive rates

Privacy and Accountability in Black-Box Medicine

Black-box medicine—the use of big data and sophisticated machine learning techniques for health-care applications—could be the future of personalized medicine. Black-box medicine promises to make it easier to diagnose rare diseases and conditions, identify the most promising treatments, and allocate scarce resources among different patients. But to succeed, it must overcome two separate, but related, problems: patient privacy and algorithmic accountability. Privacy is a problem because researchers need access to huge amounts of patient health information to generate useful medical predictions. And accountability is a problem because black-box algorithms must be verified by outsiders to ensure they are accurate and unbiased, but this means giving outsiders access to this health information. This article examines the tension between the twin goals of privacy and accountability and develops a framework for balancing that tension. It proposes three pillars for an effective system of privacy-preserving accountability: substantive limitations on the collection, use, and disclosure of patient information; independent gatekeepers regulating information sharing between those developing and verifying black-box algorithms; and information-security requirements to prevent unintentional disclosures of patient information. The article examines and draws on a similar debate in the field of clinical trials, where disclosing information from past trials can lead to new treatments but also threatens patient privacy